Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
  • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
  • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C67/00—Preparation of carboxylic acid esters
  • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
  • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
  • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C68/00—Preparation of esters of carbonic or haloformic acids
  • C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
  • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds

Definitions

• the present invention concerns a new process for the synthesis of 2,4,6-octatriene-1-oic acid and 2,4,6-octatriene-1-ol.
• 2,4,6-octatriene-1-oic acid and 2,4,6-octatriene-1-ol are compounds of pharmaceutical interest with antioxidant properties towards free radicals, for example as described in EP1501774 held by the same Applicant, anti-inflammatory activity and inhibition of the enzyme 5-alpha-reductase involved in the activation of testosterone in numerous functional regions.
• a known synthesis for obtaining said compounds is carried out by means of the corresponding aldehyde 2,4,6-octatriene-1-al. This is obtained (Kuhn, R., and Grundmann, Chem. Ber., 70, 1318 (1937)) by auto-condensation of the crotonaldehyde in the presence of pyridinium acetate as a catalyst. Said synthesis, however, does not result prevalently in one single compound but in a mixture corresponding to the various adducts deriving from the condensation of different units of crotonaldehyde.
• a mixture of aldehydes is produced with 8 atoms of carbon (2,4,6-octatriene-1-al), 12 atoms of carbon (2,4,6,8,10-dodecapentaen-1-al) and 16 atoms of carbon (2,4,6,8,10,12,14-hexadecaheptaen-1-al) deriving respectively from the condensation of 2, 3 or 4 units of crotonaldehyde, in addition to numerous other reaction by-products.
• These compounds are difficult to separate, hence the final yields, after isolation and complete purification of the compound required, are extremely low, in the order of 2-3%.
• the present invention proposes a new synthesis method for preparing the compounds described, substantially facilitating production on an industrial scale accompanied by a high yield and purity of the end product.
• the invention proposes a process for the preparation of at least one compound chosen from 2,4,6-octatriene-1-oic acid and 2,4,6-octatriene-1-ol comprising the following stages:
• the starting compound 2,4-trans-hexadienal known also as sorbic aldehyde or sorbaldehyde
• the starting compound 2,4-trans-hexadienal is condensed with triethyl phosphonoacetate, according to the Wittig-Horner scheme, in toluene and in the presence of sodium methoxide.
• the ethyl 2,4,6-trans-octatrienoate is obtained, which can be used as is or purified by crystallisation or distillation in a vacuum.
• the ethyl 2,4,6-trans-octatrienoate thus obtained is pure enough to be used directly.
• the ethyl 2,4,6-trans-octatrienoate is hydrolysed in an alkaline environment by means of sodium or potassium hydroxide in an alcoholic or hydroalcoholic solution. Normally the alkaline hydroxide is used in measured excess, at ambient temperature.
• the 2,4,6-trans-octatrienoate alkaline thus obtained can be isolated by filtration or brought directly to an aqueous solution for subsequent transformation into acid.
• the 2,4,6-trans-octatrienoate in aqueous solution is treated with diluted mineral acids, for example hydrochloric acid, until acid pH is obtained, preferably approximately 2.
• diluted mineral acids for example hydrochloric acid
• the 2,4,6-trans-octatrienoic acid precipitates and can be separated by filtration from the mother liquor or by extraction with solvents immiscible with water, such as ethyl acetate or dichloromethane. This is followed by thorough drying, under a vacuum at ambient temperature if solid or on drying agents if in solution.
• the 2,4,6-trans-octatriene-1-oic acid thus obtained can be isolated and used as it is as an active ingredient in the pharmaceutical field or it can undergo the following further stages to obtain 2,4,6-trans-octatriene-1-ol.
• the 2,4,6-trans-octatrienoic acid is placed in a solution of tetrahydrofuran (THF) and treated with triethylamine and ethyl chloroformiate, at low temperature, preferably approximately 0° C.
• THF tetrahydrofuran
• the triethylammonium hydrochloride is removed by filtration and a solution is obtained, in THF, of the mixed anhydride formed by 2,4,6-trans-octatrienoic acid and ethylcarbonic acid, which is kept at a temperature below 0° C. and used within one hour.
• said solution of mixed anhydride is treated with an aqueous solution of sodium borohydride, concentrated and stabilised with soda, maintaining a temperature below +5° C.
• the optional conclusive purification of the raw 2,4,6-trans-octatrienol occurs by crystallisation, with saturated hydrocarbons or hydroalcoholic mixtures, preferably at temperatures below 40° C. Pure 2,4,6-trans-octatrienol is obtained, with purity higher than 95%.
• a qualitative TLC analytical control is performed.
• the qualitative TLC controls use hexane/acetone in a ratio of 7/3 as eluant.
• the pH is adjusted to between 0 and 2.0 and stirring is performed for 10 minutes at approximately 20° C.
• a TLC control is performed.
• the process of the invention permits preparation of both the 2,4,6-trans-octatrienoic acid and the 2,4,6-octatrienol according to a synthesis method which substantially facilitates production and can be applied on an industrial scale, accompanied by a high yield and purity of the end product.
• the process of the invention avoids the use of large quantities of crotonaldehyde, an aggressive toxic raw material, with respect to the end product.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 2009
  • 2009-04-17 EP EP09425143A patent/EP2241543A1/de not_active Withdrawn
• 2010
  • 2010-04-16 US US13/260,260 patent/US20120022282A1/en not_active Abandoned
  • 2010-04-16 CA CA2758631A patent/CA2758631A1/en not_active Abandoned
  • 2010-04-16 EP EP10721360A patent/EP2419394A1/de not_active Withdrawn
  • 2010-04-16 JP JP2012505176A patent/JP2012524044A/ja not_active Withdrawn
  • 2010-04-16 WO PCT/EP2010/055019 patent/WO2010119117A1/en active Application Filing

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